Project Summary/Abstract Herpes simplex virus type 1 (HSV-1) is a highly successful neurotropic virus of humans that resides in the nervous system in a latent/persistent state. The morbidity of the virus infection resides with reactivation/re- emergence of the virus from latency/persistence that can result in severe and life-threatening encephalitis with profound chronic neurologic deficits in survivors. Over the past two decades, several labs have reported the generation of vaccines to HSV-1, typically subunit vaccines consisting of one or more viral-encoded glycoprotein. The experimental vaccines have been found to show various degrees of efficacy that primarily focus on sterile immunity and the CD8+ T cell response. We have recently characterized a highly efficacious vaccine, termed HSV-1 0?NLS, against challenge with a lethal dose of HSV-1 and found it to block virus shedding, replication, spread, and establishment of latency in mice challenged with 10x the LD50 of HSV-1 in comparison to naive or gD-2 subunit vaccinated mice. We propose to test the hypothesize that this vaccine generates a highly robust and efficacious immune response primarily via the production of neutralizing antibody that hinders virus infection, replication, and spread following primary infection, and restores the host immune response following therapeutic application. In this application, we will fully evaluate HSV-1 0?NLS against HSV-1 infection relative to local virus replication, spread to the central nervous system (CNS), and innate and adaptive immune responses in the trigeminal ganglion (TG) and CNS following stereotaxic injection of HSV-1 into the TG (aim 1). Furthermore, we will also characterize the role of tripartite motif-containing 21 (TRIM21) in antibody-mediated clearance of virus from infected tissue to test the hypothesis animals vaccinated with 0?NLS possess durable polyclonal antibodies (IgG) that activate the TRIM21 pathway in cells to target virus for degradation (aim 2). The results of this study will validate the pre- clinical application of this vaccine as an authentic candidate to further assess in the human patient.